Pick disease is a rare progressive dementing illness characterized by severe atrophy of the frontal and temporal lobes. Clinically, Pick disease may be difficult to distinguish from Alzheimer disease (AD). The fact that Pick disease is often familial, and the evidence suggesting that the epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for AD and possibly other dementias, prompted us to study ApoE isoforms in Pick disease. ApoE genotypes were evaluated in an autopsy series of 21 AD and 12 Pick cases and compared with published data for a large group of adults participating in the Framingham Study. The distributions of ApoE genotypes in the AD and Pick patients and the controls were significantly different from one another. The frequency of epsilon 4 was 50.0, 20.0, and 13.6% in these respective groups. Linear regression analysis showed that the number of epsilon 4 alleles was inversely related to age at onset of Pick disease (P < 0.03) and accounted for 40% of the variation in age at onset. These results suggest that epsilon 4 may be a susceptibility factor for dementia and not specifically for AD. Experiments using a monoclonal antibody against ApoE suggest that neurons and Pick bodies are immunoreactive with ApoE. The dose effect of the epsilon 4 allele on age at onset of dementias other than AD and the association of ApoE immunoreactivity with neurons and Pick bodies support a broader role for ApoE in the pathogenesis of neuronal degeneration through interactions with the neuronal cytoskeleton.